Use of fumaric acid derivatives for treating mitochondrial diseases

ABSTRACT

The present invention relates to the use of individual fumaric acid derivatives or mixtures thereof for preparing a pharmaceutical composition for treating mitochondrial diseases, especially for treating Parkinson&#39;s syndrome, Alzheimer&#39;s disease, Chorea Huntington disease, retinopathia pigmentosa and mitochondrial encephalomyopathy. Preferably, the fumaric acid derivative(s) is/are those selected from the group consisting of fumaric acid dialkyl esters or fumaric acid monoalkyl esters in the form of the free acid or a salt thereof.

This application is the section 371 national stage of PCT ApplicationPCT/EP00/12504, filed Dec. 11, 2000, the text of which is not inEnglish, which PCT Application claims priority on German Application No.100 00 577.2, filed Jan. 10, 2000, the text of which is not in English.

TECHNICAL FIELD

The present invention relates to the use of individual fumaric acidderivatives or mixtures thereof for preparing a pharmaceuticalcomposition for treating mitochondrial diseases, especially for treatingParkinson's syndrome, Alzheimer's disease, Chorea Huntington disease,retinopathia pigmentosa and mitochondrial encephalomyopathy.

BACKGROUND

The mitochondria have an independent genetic system of DNA (mtDNA) andRNA and are therefore able to synthesise certain proteins on their own.Both genes of the cell nucleus and the mitochondrial genome code for thecomponents of oxidative phosophorylation and the citrate cycle. Agenetic defect of the mtDNA may therefore affect oxidativephosphorylation and the citrate cycle, respectively, and causemalfunctions. Such defects or malfunctions have been associated with theso-called mitochondrial diseases.

Genetic defects of mtDNA may be the result of local mutation by whichone base is replaced by another. Such point mutations are associatedwith neurogenetic myasthenia, ataxia and retinopathia pigmentosa, forexample.

Genetic defects of the mtDNA may also be caused by insertion or deletionmutation where one or more nucleotides are inserted into or deleted fromthe DNA. This mutation mechanism is being discussed in connection withthe Kearns Sayre syndrome and the Pearson syndrome.

The mutation of mtDNA also plays a role in neurodegenerative diseasessuch as Parkinson syndrome, Alzheimer's disease or Chorea Huntingtondisease (Encyclopedia of Molecular Biology and Molecular Medicine, Vol.,4, Ed. R. A. Meyers). However, it has not been possible to allocate thecausative mutations to these diseases without any doubt so far. Forexample, an accumulation of mutations is also being discussed as a basisof pathogenesis.

The Parkinson syndrome exhibits a number of symptoms which may bedivided into three groups. Motoric disorders are expressed by the plussymptoms rigor (increased tonus of the striated musculature) and mediumto heavy tremor (twitching in rapid succession) and the minus symptomhypokinesia or akinesia (deterioration of the motor system, loss ofpostural reflexes). Vegetative symptoms (increased flow of saliva andtears, post-encephalitic seborrhoea) and psychic disorders (increasedindecisiveness, depressive moods, etc.) are also being observed.

The disease is based on a destruction of nerve cells in the motoric keyareas of the brain stem. In Germany, for example, about 200,000 patientsare affected. At molecular level, the Parkinson syndrome is associated,among other things, with mutations of the mitochondrial genome. It hasbeen possible to show mtDNA deletions in Parkinson patients. Inaddition, a dopamine insufficiency of certain regions of the brain isfound in cases of Parkinson syndrome. The symptoms observed are anexpression of the impaired balance between the neurohumoral transmittersubstances acetyl choline and dopamine.

At present, drug therapies are based on the inhibition of cholinergicneurotransmission with centrally acting anticholinergics, the increaseof the dopamine concentration by administration of the dopamineprecursor Levodopa and the stimulation of central dopamine receptorswith direct dopaminergic agonists.

Specific therapies therefore comprise the administration ofanticholinergics or of Levodopa. In order to favourably influence boththe plus symptoms and the minus symptom in Parkinson patients, acombination therapy is usually required which is supplemented bynon-drug therapeutic measures.

On the other hand, a therapy with anticholinergics is inadvisable forParkinson patients already suffering from marked psycho-organicdisorders or exogenpsychotic symptoms, because a worsening of thesymptoms must be expected.

Side effects limiting the therapeutic use of Levodopa are motoricsymptoms (hyperkinesia, dyskinesia), vegetative disorders(gastro-intestinal problems, among others) and cardiovascular disorders(such as orthostatic disorders).

Alzheimer's disease is pre-senile or senile dementia which progressesirreversibly and which is characterised by the destruction of areas ofthe brain. Recent studies show that, in addition to mitochondrialgenetic defects, the increased presence of the apolipoprotein E₄ (apoE₄) is related to the occurrence of Alzheimer's disease. In thehereditary form of this disease, the corresponding gene for the apo E₄is often defective. As opposed to the Parkinson syndrome, no therapyother than treatment with indomethacin is available for Alzheimer'sdisease. However, indomethacin also has considerable side effects.

Retinopathia pigmentosa is a degenerative process which is more oftenhereditary than acquired. It is associated with a narrowing of theretinal vessels, opticus atrophy, the destruction of neural elements ofthe retina and a deposition of pigments. Symptoms are nyctalopia, asevere narrowing of the field of vision and loss of sight.

Mitochondrial encephalomyopathy is a disease characterised by disordersof the mitochondrial respiratory chain. Typical symptoms are myopathy(so-called ragged red fibres myopathy), stunted growth, dementia,epileptic episodes, ataxia, focal neurological disorders and MELAS(mitochondrial encephalomyopathy, lactate acidosis and strokes).

Chorea Huntington is a hereditary dominant autosomal disease with adefect on the short arm of the 4^(th) chromosome which usually becomesmanifest between the ages of 30 and 50 and is associated withprogressive dementia. A defect or atrophy of the nucleus candatus andpossibly the nucleus lentiformis may be named as possible causes. Adefect of the neurotransmitter metabolism and the influence of mtDNAdefects are under discussion.

BRIEF SUMMARY OF THE INVENTION

Therefore, it is an object of the invention to provide a pharmaceuticalcomposition for the treatment of mitochondrial diseases, especiallythose described above, and to permit partial treatment of these diseaseswith drugs, which has not been possible so far. It is another object ofthe invention to provide a pharmaceutical preparation for the treatmentof the above diseases which reduces the side effects of existing drugtherapies and does not require a combination therapy.

The object of the present invention is achieved by the use of individualor a mixture of fumaric acid derivative(s) for preparing apharmaceutical composition for treating mitochondrial diseases,especially for treating Alzheimer's disease, Parkinson's syndrome,Chorea Huntington disease, retinopathia pigmentosa and mitochondrialencephalomyopathy. The subject matters of the invention arecharacterised in detail in the claims.

FURTHER DETAILED DESCRIPTION OF THE INVENTION

It is known that pharmaceutical preparations which, upon biologicaldegradation after administration, enter into the citric acid cycle orare part thereof gain increasing therapeutic significance—especiallywhen given in high dosages—since they can alleviate or heal diseasescaused cryptogenetically.

For example, fumaric acid inhibits the growth of the Ehrlich ascitestumour in mice, reduces the toxic effects of mitomycin C and aflatoxinand displays anti-psoriatic and anti-microbial activity. In general, thetreatment of psoriasis with different fumaric acid derivatives hasalready been described in a number of patents, e.g. EP 0 188 749, DE 2530 372, DE 26 21 214 or EP 0 312 697.

Another use of certain fumaric acid derivatives, namely of the alkylhydrogen fumarates, is disclosed in DE 197 21 099.6 and DE 198 53 487.6according to which these specific fumaric acid derivatives are describedfor treating auto-immune diseases such as polyarthritis, multiplesclerosis and graft-versus-host reactions. In addition, DE 198 53 487.6and DE 198 39 566.3 teach the use of alkyl hydrogen fumarates anddialkyl fumarates in transplantation medicine.

Surprisingly, it has now been found that individual fumaric acidderivatives or mixtures thereof may advantageously be used for preparinga pharmaceutical preparation for treating mitochondrial diseases,especially for treating the Parkinson syndrome, Alzheimer's disease,Chorea-Huntington disease, retinopathia pigmentosa or mitochondrialencephalomyopathy.

In the invention, one or more fumaric acid dialkyl esters and/or fumaricacid monoalkyl esters in the form of the free acid or in the salt formare preferably used for preparing the pharmaceutical composition.

The fumaric acid dialkyl esters preferably correspond to the formula:

wherein R₁ and R₂ which may be the same or different independentlyrepresent a linear, branched, saturated or unsaturated C₁₋₂₄ alkylradical or a C₅₋₅₀ aryl radical and wherein these radicals areoptionally substituted with halogen (F, Cl, Br, I), hydroxy, C₁₋₄alkoxy, nitro or cyano.

The radicals R₁ and R₂ preferably are methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl,2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl,allyl, 2-hydroxyethyl, 2- and/or 3-hydroxypropyl, 2-methoxyethyl,methoxymethyl or 2- or 3-methoxypropyl.

The fumaric acid monoalkyl esters preferably correspond to the formula:

wherein R₁ is a radical as defined above; A is hydrogen or an alkalineor alkaline earth metal cation or a physiologically acceptabletransition metal cation, preferably selected from Li⁺, Na⁺, K⁺, Mg²⁺,Ca²⁺, Zn²⁺, Fe²⁺, Mn²⁺ and n is 1 or 2 and corresponds to the valence ofA.

Preferably the fumaric acid derivatives of the invention are used insuch an amount that one dosage unit of the pharmaceutical compositioncontains an amount of one or more fumaric acid derivative(s) whichcorresponds or is equivalent to 1 to 500 mg, preferably 10 to 300 mg andmost preferably 10 to 200 mg of fumaric acid.

Applications are preferred where the pharmaceutical composition isadministered orally, parenterally, rectally, transdermal or ophthally(in the form of eye drops), oral administration being preferred. Thepreparation is present in the form suitable for the pertinent form ofadministration.

In case of oral administration the pharmaceutical composition of theinvention is present in the form of unit dosage tablets, micro-tabletsor micro-tablets (micro-pellets) or granulate which may optionally beencapsulated or filled into sachets, capsules or solutions for drinking.

In a preferred embodiment, solid dosage forms or forms ofadministration, respectively, are provided with an enteric coating. Sucha coating may also be applied to the encapsulated or filled dosageforms.

According to the invention, one or more fumaric acid derivative(s)is/are preferably used which are selected from the group comprisingfumaric acid dimethyl ester, fumaric acid diethyl ester, fumaric acidmethyl ethyl ester, methyl hydrogen fumarate, ethyl hydrogen fumarate,magnesium methyl fumarate, magnesium ethyl fumarate, zinc methylfumarate, zinc ethyl fumarate, iron methyl fumarate, iron ethylfumarate, calcium methyl fumarate and/or calcium ethyl fumarate.

The pharmaceutical composition of the invention may preferably contain10 to 500 mg of dialkyl fumarate, especially dimethyl fumarate and/ordiethyl fumarate; 10 to 500 mg of calcium alkyl fumarate, especiallycalcium methyl fumarate and/or calcium ethyl fumarate, 0 to 250 mg ofzinc alkyl fumarate, especially zinc methyl fumarate and/or zinc ethylfumarate, 0 to 250 mg of alkyl hydrogen fumarate, especially methylhydrogen fumarate and/or ethyl hydrogen fumarate and 0 to 250 mg ofmagnesium alkyl fumarate, especially magnesium methyl fumarate and/ormagnesium ethyl fumarate; the total of the amounts specifiedcorresponding to an equivalent of 500 mg, preferably 300 mg and mostpreferably 200 mg of fumaric acid.

Preferred compositions according to the invention contain only methylhydrogen fumarate or dimethyl fumarate in an amount of 10 to 300 mg.

For example, the fumaric acid derivatives are prepared according to themethod described in EP 0 312 679.

In order to illustrate the use according to the invention, variousexamples for preparing preferred drugs are given below.

EXAMPLE 1 Preparation of Film Tablets with an Enteric Coating Containing100.0 mg of Monomethyl Fumarate-Ca Salt, which Corresponds to 78 mg ofFumaric Acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 10.000 kg of monomethyl fumarate-Ca salt are crushed,mixed intensely and homogenised by means of a sieve 800. Then anexcipient mixture of the following composition is prepared: 21.000 kg ofstarch derivative (STA-RX 1500®), 2.000 kg of micro-crystallinecellulose (Avicel PH 101®), 0.600 kg of polyvinyl pyrrolidone (PVP,Kollidon® 25), 4.000 kg of Primogel®, 0.300 kg of colloidal silicic acid(Aerosil®).

The active ingredient is added to the entire powder mixture, mixed,homogenised by means of a sieve 200 and processed with a 2% aqueoussolution of polyvinyl pyrrolidone (PVP, Kollidon® 25) in the usualmanner into binder granules, and then mixed with the outer phase in adry state. The latter consists of 2.000 kg of a so-called FST complexcontaining 80% of talcum, 10% of silicic acid and 10% of magnesiumstearate.

Thereafter the mixture is pressed into convex tablets with a weight of400 mg and a diameter of 10.0 mm by the usual method. Instead of theseclassic compaction methods, other methods such as direct compaction orsolid dispersions according to the melting and spray drying method mayalso be used for preparing tablets.

Enteric Coating:

A solution of 2.250 kg of hydroxy propyl methyl cellulose phthalate(HPMCP, Pharmacoat HP® 50) is dissolved in a solvent mixture consistingof 2.50 liters of demineralised water, 13.00 liters of acetone Ph. Helv.VII and 13.00 liters of ethanol (94% by weight) and then 0.240 kg ofcastor oil (Ph. Eur. II) is added to the solution. The solution ispoured or sprayed in portions onto the tablet cores in a coating pan ina conventional manner or applied by means of a fluidised-bed apparatusof the appropriate structure.

After drying, the film coating is applied. Said coating consists of asolution of Eudragit E 12.5%® 4.800 kg, talcum Ph. Eur. II 0.340 kg,titanium(VI) oxide Cronus RN 56® 0.520 kg, coloured lacquer ZLT-2 blue(Siegle) 0.210 kg, and polyethylene glycol 6000 Ph. Helv. VII 0.12 kg ina solvent mixture of 8.200 kg of 2-propanol Ph. Helv. VII, 0.06 kg ofglycerine triacetate (Triacetin®) and 0.200 kg of demineralised water.After homogenous distribution in the coating pan or the fluidised bed,the mixture is dried and polished in the usual manner.

EXAMPLE 2 Preparation of Enteric Coated Capsules Containing 86.5 mg ofMonoethyl Fumarate-Ca Salt and 110.0 mg of Dimethyl Fumarate, whichCorresponds to a Total of 150 mg of Fumaric Acid

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 8.650 kg of monoethyl fumarate-Ca salt and 11.000 kg ofdimethyl fumarate are intensely mixed with a mixture consisting of15.000 kg of starch, 6 kg of lactose Ph. Helv. VII, 2 kg ofmicro-crystalline cellulose (Avicel®), 1 kg of polyvinyl pyrrolidone(Kollidon® 25) and 4 kg of Primogel® and homogenised by means of a sieve800.

Together with a 2% aqueous solution of polyvinyl pyrrolidone (Kollidon®25) the entire powder mixture is processed in the usual manner into abinder granulate and mixed with the outer phase in the dried state. Saidouter phase consists of 0.350 kg of colloidal silicic acid (Aerosil®),0.500 kg of Mg stearate and 1.500 kg of talcum Ph. Helv. VII. Thehomogeneous mixture is then filled in portions of 500.0 mg intoappropriate capsules which are then provided with an enteric(gastric-acid resistant) coating consisting of hydroxy propyl ethylcellulose stearate and castor oil as softening agent by a known method.Instead of hard gelatine capsules, the mixture may also be filled intoappropriate gastric acid-resistant capsules, which consist of a mixtureof cellulose acetate phthalate (CAP) and hydroxy propyl ethyl cellulosephthalate (HPMCP).

EXAMPLE 3 Preparation of Enteric-coated Micro-tablets in CapsulesContaining 87.0 mg of Monoethyl Fumarate-Ca Salt, 120 mg of DimethylFumarate, 5.0 mg of Monoethyl Fumarate-Mg Salt and 3.0 mg of MonoethylFumarate-Zn Salt, which Corresponds to a Total of 164 mg of Fumaric Acid(“forte” Tablets)

Taking the necessary precautions (breathing mask, gloves, protectiveclothing, etc.), 8.700 kg of monoethyl fumarate-Ca salt, 12.000 kg ofdimethyl fumarate, 0.500 kg of monoethyl fumarate-Mg salt and 0.300 kgof monoethyl fumarate-Zn salt are crushed, intensely mixed andhomogenised by means of an sieve 800. Then an excipient mixture of thefollowing composition is prepared: 18.00 kg of starch derivative (STA-RX1500), 0.30 kg of micro-crystalline cellulose (Avicel PH 101), 0.75 kgof PVP (Kollidon 120), 4.00 kg of Primogel, 0.25 kg of colloidal silicicacid (Aerosil). The entire powder mixture is added to the activeingredient mixture, homogenised by means of a 200 sieve, processed inthe usual manner with a 2% aqueous solution of polyvinyl pyrrolidone(Kollidon K25) to obtain a binder granulate and mixed in a dry statewith the outer phase consisting of 0.50 kg of magnesium stearate and1.50 kg of talcum. Then the powder mixture is pressed by theconventional method into convex micro-tablets with a gross mass of 10.0mg and a diameter of 2.0 mm. Instead of this classic tabletting methodother methods for making tablets such as direct tabletting or soliddispersions by the melt method and the spray drying method may also beused.

The gastric acid-resistant coating may be poured or sprayed on in aclassic coating pan or applied in a fluidised-bed apparatus. In order toachieve resistance to gastric acid, portions of a solution of 2.250 kgof hydroxy propyl methyl cellulose phthalate (HPMCP, Pharmacoat HP 50)are dissolved in a mixture of the following solvents: acetone 13.00 l,ethanol 94% by weight denatured with 2% ketone 13.50 l and demineralisedwater 2.50 l. 0.240 kg of castor oil are added as softening agent to thefinished solution and applied in portions to the tablet cores in theusual manner.

Film-coat: After drying is completed, a suspension of the followingcomposition is applied as a film-coat in the same apparatus: talcum0.340 kg, titanium(VI) oxide Cronus RN 56 0.4 kg, coloured lacquer L redlacquer 86837 0.324 kg, Eudragit E 12.5% 4.800 kg and polyethyleneglycol 6000 pH 11 XI 0.12 kg in a solvent mixture of the followingcomposition: 2-propanol 8.170 kg, aqua demineralisata 0.20 kg andglycerine triacetate (Triacetin) 0.600 kg.

The gastric acid-resistant micro-tablets are then filled into hardgelatine capsules at a net weight of 500.0 mg and sealed.

EXAMPLE 4

Example 4 shows the stimulating influence of fumaric acid derivatives onthe enzyme activity of succinate dehydrogenase.

Succinate dehydrogenase is part of the mitochondrial membrane andcatalyses the dehydration of succinic acid to fumaric acid within thecitrate cycle. Hydrogen is passed to the respiratory chain via theelectron transfer flavoprotein. Thus, the activity of succinatedehydrogenase may influence the electron flow of the electron transportchain. The latter, in turn, is linked to the process of oxidativephosphorylation, the malfunction of which is considered a cause formitochondrial diseases. Consequently, the activity of succinatedehydrogenase may also have an effect on oxidative phosphorylation.

The following table 1 shows an evaluation of the stimulating influenceof fumaric acid derivatives on the enzyme activity of the succinatedehydrogenase.

Fumarates Fibroblasts [0.75 m Val/I] Dimethyl fumarate strong (838%)Calcium monoethyl fumarate medium Magnesium monoethyl fumarate weak Zincmonoethyl fumarate strong (107%) Monoethyl fumarate weak

1. A method of treating a patient suffering from a mitochondrialdisease, said method comprising administering to said patient apharmaceutical composition comprising (i) an individual fumaric acidderivative or (ii) a mixture of fumaric acid derivatives, wherein said(i) or (ii) is selected from the group consisting of (a) fumaric aciddiesters of the formula:

wherein R₁ and R₂ which may be the same or different independentlyrepresent a linear, branched, cyclic, saturated or unsaturated C₁₋₂₄alkyl radical or a C₅₋₂₀ aryl radical and wherein these radicals areoptionally substituted with halogen (F, Cl, Br, I), hydroxy, C₁₋₄alkoxy, nitro or cyano; and (b) fumaric acid monoesters of the formula:

wherein R₁ is as defined hereinabove, A is hydrogen or an alkali oralkaline earth metal cation or a physiologically-acceptable transitionmetal cation, and n is 1 or 2 and corresponds to the valence of A;wherein the mitochondrial disease is selected from the group consistingof Parkinson's syndrome, Alzheimer's disease, Chorea Huntington disease,retinopathia pigmentosa, and mitochondrial encephalomyopathy, andwherein one dosage unit of the pharmaceutical composition contains anamount of said fumaric acid derivative(s) which corresponds to 1 to 500mg of fumaric acid.
 2. The method according to claim 1 wherein thefumaric acid derivative(s) in the pharmaceutical compositioncorrespond(s) to the formula of (a).
 3. The method according to claim 2wherein the radicals R₁ and R₂ are methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl,cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl,methoxymethyl, 2-methoxypropyl, or 3-methoxypropyl.
 4. The methodaccording to claim 1 wherein the fumaric acid derivative(s) in thepharmaceutical composition correspond(s) to the formula of (b).
 5. Themethod according to claim 4 wherein A is one of Li^(⊕), Na^(⊕), K^(⊕),Mg^(2⊕), Ca^(2⊕), Zn^(2⊕), Mn^(2⊕).
 6. The method according to any ofclaims 1-4 wherein said dosage unit of the pharmaceutical compositioncontains an amount of fumaric acid derivative(s) which corresponds to 10to 300 mg of fumaric acid.
 7. The method according to any of claims 1-4wherein said pharmaceutical composition is adapted for and isadministered by oral, parenteral, rectal, transdermal or ophthaladministration.
 8. The method according to any of claims 1-4 whereinsaid pharmaceutical composition is adapted for and is administered byoral administration.
 9. The method according to any of claims 1-4wherein said pharmaceutical composition is adapted for and isadministered by oral administration, and wherein the dosage unit of thepharmaceutical composition administered contains an amount of fumaricacid derivative(s) which corresponds to 10 to 300 mg of fumaric acid.10. The method according to claim 7 where the pharmaceutical compositionfor oral administration is present in the form of unit dosage tablets,micro-tablets or micro-pellets optionally encapsulated or filled intosachets, capsules or solutions for drinking.
 11. The method according toclaim 10 wherein the dosage unit of the pharmaceutical compositionadministered contains an amount of fumaric acid derivative(s) whichcorresponds to 10 to 300 mg of fumaric acid.
 12. The method according toclaim 10 wherein the dosage forms thereof that are solids are providedwith an enteric coating.
 13. The method according to claim 12 whereinthe dosage unit of the pharmaceutical composition administered containsan amount of fumaric acid derivative(s) which corresponds to 10 to 300mg of fumaric acid.
 14. The method according to claim 1 wherein thefumaric acid derivative selected for administration comprises one ormore of the following: fumaric acid dimethyl ester, fumaric acid diethylester, fumaric acid methyl ethyl ester, methyl hydrogen fumarate, ethylhydrogen fumarate, calcium methyl fumarate, calcium ethyl fumarate,magnesium methyl fumarate, magnesium ethyl fumarate, zinc methylfumarate, zinc ethyl fumarate, iron methyl fumarate, iron ethylfumarate.
 15. The method according to claim 1 wherein the dosage unitsof the pharmaceutical composition contain either individually or in amixture of any two or more of the following active ingredient(s): 10 to500 mg of dialkyl fumarate; 10 to 500 mg of calcium alkyl fumarate; 0 to250 mg of zinc alkyl fumarate; 0 to 250 mg of alkyl hydrogen fumarate; 0to 250 mg of magnesium alkyl fumarate;

the total amount of the active ingredient(s) administered correspondingto an equivalent of not more than 500 mg of fumaric acid.
 16. The methodaccording to claim 15 wherein said total amount of the activeingredient(s) administered corresponds to an equivalent of not more than300 mg of fumaric acid.
 17. The method according to claim 15 whereinsaid total amount of the active ingredient(s) administered correspondsto an equivalent of not more than 200 mg of fumaric acid.
 18. The methodaccording to claim 1 wherein the dosage units of the pharmaceuticalcomposition contain either individually or in a mixture of any two ormore of the following active ingredient(s): 10 to 500 mg of dimethylfumarate and/or diethyl fumarate; 10 to 500 mg of calcium methylfumarate and/or calcium ethyl fumarate; 0 to 250 mg of zinc methylfumarate and/or zinc ethyl fumarate; 0 to 250 mg of methyl hydrogenfumarate and/or ethyl hydrogen fumarate; 0 to 250 mg of magnesium methylfumarate and/or magnesium ethyl fumarate; the total amount of the activeingredient(s) administered corresponding to an equivalent of not morethan 500 mg of fumaric acid.
 19. The method according to claim 18wherein said total amount of the active ingredient(s) administeredcorresponds to an equivalent of not more than 300 mg of fumaric acid.20. The method according to claim 18 wherein said total amount of theactive ingredient(s) administered corresponds to an equivalent of notmore than 200 mg of fumaric acid.
 21. The method according to claim 18wherein said active ingredient is dimethyl fumarate, or diethylfumarate, or both, and wherein said active ingredient is in the form ofunit dosage tablets, micro-tablets or micro-pellets.
 22. The methodaccording to claim 21 wherein said active ingredient(s) is dimethylfumarate.